Anthracyclines are a class of antibiotics derived from certain types of Streptomyces bacteria. Anthracyclines are often used as cancer therapeutics and function in part as nucleic acid intercalating agents and inhibitors of the DNA repair enzyme topoisomerase II, thereby damaging nucleic acids in cancer cells, preventing the cells from replicating. One example of an anthracyc line cancer therapeutic is doxorubicin, which is used to treat a variety of cancers including breast cancer, lung cancer, ovarian cancer, lymphoma, and leukemia. The 6-maleimidocaproyl hydrazone of doxorubicin (DOXO-EMCH also known as aldoxorubicin or INNO-206) was synthesized to provide an acid-sensitive linker that could be used to prepare immunoconjugates of doxorubicin and monoclonal antibodies directed against tumor antigens (Willner et al., Bioconjugate Chem 4:521-527 (1993)). In this context, antibody disulfide bonds are reduced with dithiothreitol to form free thiol groups, which in turn react with the maleimide group of DOXO-EMCH to form a stable thioether bond. When administered, the doxorubicin-antibody conjugate is targeted to tumors containing the antigen recognized by the antibody. Following antigen-antibody binding, the conjugate is internalized within the tumor cell and transported to lysosomes. In the acidic lysosomal environment, doxorubicin is released from the conjugate intracellularly by hydrolysis of the acid-sensitive hydrazone linker. Upon release, the doxorubicin reaches the cell nucleus and is able to kill the tumor cell. For additional description of doxorubicin and DOXO-EMCH see, for example, U.S. Pat. Nos. 7,387,771 and 7,902,144 and U.S. patent application Ser. No. 12/619,161, each of which is incorporated in their entirety herein by reference.
Further, DOXO-EMCH has been conjugated in vitro with human serum albumin (HSA) to form a stable thioether conjugate (Kratz et al., J Med Chem 45:5523-5533 (2002)).
Brain tumors, including malignant gliomas in particular, are among the most aggressive human cancers and are rarely curable (DeAngelis et al., N. Engl. J. Med. 2001, 344, 114-123; Nelson et al., J. Neurooncol. 1985, 3, 99-103; Kornblith et al., J. Neurosurg. 1988, 68, 1-17). The median survival after diagnosis is about 12-14 months. Treatment with chemotherapeutic drugs such as nitrosoureas, platinum compounds, and temozolomide, increases the survival time of patients only marginally (Huncharek et al., Anticancer Res. 1998, 18, 4693-4697; Brandes et al., Anticancer RES. 2000, 20, 1913-1920). Further complicating treatment of brain cancers is the inability of many drugs to cross the blood-brain barrier (BBB). The BBB consists of tight junctions around the capillaries and protect the brain against changes in the levels of certain substances like ions, or against infections. The endothelial cells restrict the diffusion of large molecules such as albumin, while allowing the diffusion of smaller molecules such as O2 or CO2. Glioblastoma cell lines were driven to apoptosis following growth arrest induced by doxorubicin (Stan et al., Anticancer Res., 1999, 19, 941-950). However, doxorubicin lacks the ability to cross the BBB, because it is a substrate of the P-glycoprotein efflux pumps (Sardi et al., Cancer Chemother. Pharmacol., 2011, 67, 1333-1340). Free doxorubicin concentration in glioma tissues is below effective levels and doxorubicin has no effect on glioblastoma growing in the brain (Steiniger et al., Int. J. Cancer, 2004, 109, 759-767; Von Hoist, Acta Neurochirr., 1990, 104, 13-16). Therefore, the development of a strategy allowing drug delivery across the BBB is of prime importance. Hence, the need for efficient carriers to transport anticancer drugs, such as doxorubicin, into the brain remains high.